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| Home > Publications database > Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease |
| Journal Article | FZJ-2024-03601 |
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2024
American Medical Association
Chicago, Ill.
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Please use a persistent id in citations: doi:10.1001/jamaneurol.2023.4398 doi:10.34734/FZJ-2024-03601
Abstract: IMPORTANCE Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase.OBJECTIVE To investigate whether a-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia.DESIGN, SETTING, AND PARTICIPANTS This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson·s Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122)included participants with iRBD and controls and the second (n = 263) included nonmanifestGBAN/ o4 s9 gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBAIN 4095 gene carriers, 21 GBAIN 4095 gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1. participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants,4 were excluded due to alternative diagnoses.EXPOSURES Clinical assessments, imaging, and serum collection.MAIN OUTCOME AND MEASURES LlCAM-positive extracellular vesicles (LlEV) were immunocaptured from serum. a-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% Cis evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between LlEV a-synuclein and prodromal markers.RESULTS Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68 .4%), and 182 were female (31.6%). A derived threshold of serum LlEV a-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% Cl, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% Cl. 0.71-0.89) . Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased LlEV a-synuclein levels. Across all cohorts, LlEV a-synuclein differentiated participants with more than 80% probability of having prodromal PD from current andhistoric healthy control populations (AUC = 0.90; 95% Cl, 0 .87-0 .93), irrespective of initialdiagnosis. LlEV a-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases(n = 40) that phenoconverted to PD or related dementia.CONCLUSIONS AND RELEVANCE LlEVa-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.
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